Enhancement of radiation induced cell death in chicken B lymphocytes by withaferin A.

Withaferin A (WA), a plant withanolide, has shown significant radiosensitizing effect in vitro and in vivo. Inhibition of DNA repair has been suggested as a mechanism of radiosensitization by WA. To test this, the effect of withaferin A on survival of DT40 chicken B-lymphocyte cell line and its repair deficient single gene mutants Rad54-/-, Ku70-/- and double mutant Ku70-/- /Rad54-/- after irradiation was studied. Exponentially growing cells were treated for 1 hr with 5 microM WA and then exposed to different doses of X-rays. Cell survival was studied by clonogenic assay. WA significantly reduced survival of DT40, Ku70-/- and Ku70-/- /Rad54-/-, but not Rad54-/- cells, suggesting that WA enhances radiosensitivity by interfering with homologous repair, the major pathway of DSB repair in these cells. Inhibition of DNA repair is further indicated in a significant decrease in surviving fraction of DT40 cells by post-irradiation incubation with WA. This could have relevance to cancer radiotherapy.

Radiosensitization of a mouse melanoma by withaferin A: in vivo studies.

The radiosensitizing effect of a plant withanolide, withaferin A, on the B16F1 mouse melanoma was studied in vivo. Treatment of 100 mm3 tumours with 10 to 60 mg/kg withaferin A intraperitoneally produced a dose dependent increase in growth delay and volume doubling time. Injection of 30-50 mg/kg withaferin A, followed by 30 Gy local gamma irradiation, significantly enhanced the tumour response. No systemic or local adverse reactions were noted in these groups. The drug was most effective when injected intraperitoneally 1 h before irradiation. However, neither the individual agents nor their combination could produce any complete response (tumour cure). Melanoma is a relatively radioresistant tumour. The present results indicate that the radiation response of this tumour can be significantly enhanced by pretreatment with withaferin A.

Effect of withafastuosin E on gastric mucosal offensive and defensive factors in rats.

Withafastuosin E (WE), a withanolide of Datura fastuosa, has been reported to possess anti-stress activity and augment prostaglandins. The present investigation has been undertaken to evaluate the anti-ulcer activity and its mechanism in various models of experimentally induced ulcers in rats. WE (20 mg/kg, po) reduced the incidence of ulcer and ulcer index significantly in rats. The drug also decreased volume of gastric secretion, acid and peptic output, though it did not affect mucin secretion or mucosal glycoprotein content in terms of total carbohydrate:protein ratio or gastric cell shedding (in terms of gastric juice DNA content) or cell replication (in terms of microgram DNA/mg of protein). The results suggest significant anti-ulcer activity of WE which may be due to its effect on decreasing the offensive acid-pepsin factors.

Antioxidant activity of glycowithanolides from Withania somnifera.

Antioxidant activity of active principles of Withania somnifera, consisting of equimolar concentrations of sitoindosides VII-X and withaferin A, was investigated for their effects on rat brain frontal cortical and striatal concentrations of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX). Results were compared with effects induced by deprenyl, an agent with well documented antioxidant activity. Active glycowithanolides of W. somnifera (WSG) (10 and 20 mg/kg, i.p.), administered once daily for 21 days, induced a dose-related increase in SOD, CAT and GPX activity in frontal cortex and striatum, which was statistically significant on days 14 and 21, except with the lower dose of WSG on GPX activity, where the effect was evident only on day 21. The data were comparable to those induced by deprenyl (2 mg/kg/day, i.p.) with respect to SOD, CAT and GPX activities, which were evident by day 14. These findings are consistent with the therapeutic use of W. somnifera as an Ayurvedic rasayana and medhyarasayana. Antioxidant effect of active principles of W. somnifera may explain, at least in part, the reported antistress, immunomodulatory, cognition-facilitating, anti-inflammatory and anti-aging effects produced by them in experimental animals, and in clinical situations.

Withania somnifera Dunal (Ashwagandha): potential plant source of a promising drug for cancer chemotherapy and radiosensitization.

Study of antitumor and radiosensitizing properties of W. somnifera (Ashwagandha), a well known medicinal plant, have yielded encouraging results. The alcoholic extract of the dried roots of the plant as well as the active component withaferin A isolated from the extract showed significant antitumor and radiosensitizing effects in experimental tumors in vivo, without any noticeable systemic toxicity. Withaferin A gave a sensitizer enhancement ratio of 1.5 for in vitro cell killing of V79 Chinese hamster cells at a non toxic concentration of approximately 2 microM. The mechanism of action of this compound is not known. The studies so far indicate that W. somnifera could prove to be a good natural source of a potent and relatively safe radiosensitizer/chemotherapeutic agent. Further studies are needed to explore the clinical potential of this plant for cancer therapy.

Cardiovascular effects of a withanolide from Withania coagulans, dunal fruits.

A new withanolide, with a unique chemical structure similar to the aglycones of the cardiac glycosides, with mol. wt. 488 6, m. p. 260-261 degrees, isolated from the fruits of Withania coagulans, was screened for cardiovascular effects. At doses of 5 mg/kg body weight, the withanolide produced a moderate fall of blood pressure in dogs (34 +/- 2.1, mm Hg) which was blocked by atropine and not by mepyramine or propranolol. In rabbit Langendorff preparation and ECG studies, it produced myocardial depressant effects but in perfused frog heart it produced mild positive inotropic and chronotropic effects.